Alzheimer disease is a neurodegenerative disease having pathological features such as degeneration or loss of nerve cells, formation of senile plaques and neurofibrillary tangles. Alzheimer disease causes symptoms of dementia such as gradual loss of memory, recognition, thinking, judgment or the like, and it eventually leads to death. No effective method for treating or preventing this disease has hitherto been known.
The main protein constituting a senile plaque deposited in the brain is β-amyloid protein (amyloid β protein, Aβ) which is composed of from 39 to 43 amino acids. β-Amyloid protein exhibits cytotoxicity, which is presumed to induce Alzheimer disease (Non-patent Document 1). β-Amyloid protein secreted from cells is a polypeptide composed mainly of 40 or 42 amino acids and particularly, that composed of 42 amino acids is known to deposit in the brain quickly because of strong aggregation property and in addition, have strong cytotoxicity (Non-patent Document 2). Amyloid protein is produced ubiquitously in vivo, but its function remains unknown.
β-Amyloid protein is produced by processing of an amyloid precursor protein (APP) which is a membrane protein. Mutation of an APP gene is observed from patients suffering from familial Alzheimer disease. An increase in the production or secretion amount of β-amyloid protein is known to occur in the cells having this mutated APP gene introduced therein. This suggests that a medicament inhibiting the production or secretion of β-amyloid protein is effective for the prevention or treatment of Alzheimer disease.
In the processing step of an amyloid precursor protein to produce β-amyloid protein, BACE (β-site APP Cleaving Enzyme) (Non-patent Document 3) or Asp1 (Non-patent Document 4), each an aspartic protease, is reported as a β secretase for cleaving the N terminal of β-amyloid protein. It is suggested strongly that γ-secretase which cleaves the C-terminal region is partially composed of presenilin (Non-patent Document 5). Although inhibitors of β-secretase and γ-secretase have been reported (Non-patent document 6), most of them are peptide like compounds.
In Patent document 1, SMITH, et al., disclose compounds having a sulfonamide skeleton and capable of controlling production of β-amyloid protein. In Patent Document 2, BELANGER, et al., disclose compounds having a bicycloalkylsulfonamide skeleton and inhibiting γ-secretase. Also in Patent Documents 3, 4 and 5, diarylsulfone compounds inhibiting γ-secretase are disclosed. In Patent Document 6, thionaphthalene derivatives inhibiting aggregation of amyloid protein are disclosed.    Non-patent Document 1: Science, 259, 514(1993)    Non-patent Document 2: Journal of Biological Chemistry, 270, 7013(1995)    Non-patent Document 3: Science, 286, 735(1999)    Non-patent Document 4: Molecular and Cellular Neuroscience, 16, 609(2000)    Non-patent Document 5: Journal of Medicinal Chemistry, 44, 2039(2001)    Patent Document 1: WO00/50391    Patent Document 2: WO01/70677    Patent Document 3: WO02/081433    Patent Document 4: WO02/081435    Patent Document 5: WO03/18543    Patent Document 6: JP-A-1997-95444